Hutchinson-Gilford progeria syndrome (HOPS) is a rare genetic disorder characterized by dramatic premature aging. Patients with HGPS appear normal at birth, but begin to display alopecia, growth retardation, bone abnormalities, osteoporosis, and sclerodermatous skin by one year of age. On average, death occurs at the age of 12 from heart attack or stroke. Classic HGPS is caused by a de novo point mutation in exon 11 (1824, C->T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A protein termed progerin that lacks the normal cleavage site to remove a C-terminal farnesyl group. My long-term research objective is to uncover the cellular mechanisms underlying HGPS and normal aging. In specific aim 1, we propose to analyze the defects caused by progerin and identify progerin interacting partners. A cohnbined cellular biological and biochemical approaches will be taken to achieve this aim. In specific aim 2, we will investigate the role of progerin in the normal aging process. We propose that progerin is produced in normal cells, and is causatively associated with senescence of those cells that express it. To test this idea, we will investigate how progerin is produced in the normal cells, and the functional relationship between jsrogerin and normal aging. In specific aim 3, we propose to generate highresolution, genome-wide maps of the alterations of chromatin structure and gene expression in HGPS cells using an approach that couples chromatin immunoprecipitation with next-generation sequencing (ChlP-seq) as well as gene expression analysis. Data from these high-throughput analysis will provide valuable information on when and how the changes of chromatin structure happen in HGPS cells, and which essential genes/pathways are affected in HGPS cells.